Cytotoxic T lymphocytes and T-helper lymphocytes appear to play important roles in controlling HIV infection. The overall objective of this project is to develop an effective immunotherapeutic approach to HIV infection by utilizing a novel antigen delivery system in combination with dendritic cells (DC) to induce HIV-specific T cell mediated immunity. DC are extraordinarily efficient antigen presenting cells. Our group has developed methods for obtaining FDC from peripheral blood and shown that these cells, but not monocytes or B cells, can sensitize naive T cells to nominal antigens in vitro leading to generation of CTL and T helper cell lines. We have shown that HIV specific CTL can be generated in vitro using a DC based system of antigen presentation, and the resultant TL effectors can lyse HIV infected autologous EBV-transformed B cells. We have also shown in patients with HIV infection that infusion of DC pulsed with HIV antigens is safe, and can leaf to increased T cell responses to these antigens. Recently, we have developed a novel method by which exogenous proteins coupled to a peptide derived from HIV-1 tat can be transported into DC for processing and presentation of both CTL and helper epitopes. We believe that the combination of our protein delivery system and DC based HIV antigen (modified HIV envelope) presentation provides a platform for the development of an effective immunotherapeutic approach to HIV infection. The proposed experiments will evaluate the feasibility of this approach in vitro in a human assay system and in vivo in a mouse model. These results of these studies should provide the basis for expanding clinical trials with HIV antigen pulsed DC in patients with HIV infection.